E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Low blood pressure due to severe infection |
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E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028237 |
E.1.2 | Term | Multiple organ failure |
E.1.2 | System Organ Class | 100000004867 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040070 |
E.1.2 | Term | Septic shock |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objectives of this trial are:
1. To ascertain if levosimendan reduces the incidence and severity of organ failure as compared to placebo in adult patients who have septic shock. 2. To identify the effect of levosimendan on the function of individual organs function in septic shock. 3. To establish the safety profile and the metabolism of levosimendan by the body in this group of patients.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this trial are:
1. To identify whether levosimendan reduces the need for and duration of blood pressure support with conventional adrenaline-like drugs called catecholamines and whether levosimendan reduces the damage to the heart that is associated with septic shock and the use of these drugs. 2. To establish whether levosimendan affects the degree of inflammation that is seen in septic shock by measuring the levels of chemicals that are released in response to overwhelming infection. 3. To collect longer-term (3 and 6 month) outcome data to help inform the appropriate outcome measure for a subsequent larger trial if the efficacy of levosimendan is confirmed in this study.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The target population is adult patients (≥18 years) who require vasopressor support for the management of sepsis despite fluid resuscitation. Inclusion criteria will use the internationally-established consensus definitions of sepsis. In brief:
Fulfil 2/4 of the criteria of the systemic inflammatory response syndrome (SIRS) due to known or suspected infection within the previous 24 hours. The SIRS criteria are: (1) fever (>38 C) or hypothermia (< 36 C), (2) tachycardia (heart rate > 90 beats per minute), (3) tachypnoea (respiratory rate > 20 breaths per minute or PaCO2 < 4.3 kPa) or need for mechanical ventilation, (4) abnormal leukocyte count (> 12,000 cells/mm3, < 4000 cells/mm3, or > 10% immature [band] forms).
Hypotension, despite adequate intravenous fluid resuscitation, requiring treatment with a vasopressor infusion (e.g. noradrenaline / adrenaline / vasopressin analogue) for at least four hours and still having an ongoing vasopressor requirement at the time of randomisation.
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E.4 | Principal exclusion criteria |
The exclusion criteria are as follows:
1. More than 24 hours since meeting all the inclusion criteria 2. End-stage renal failure at presentation (previously dialysis-dependent). 3. Severe hepatic impairment (Child-Pugh class C). 4. A history of Torsades de Pointes. 5. Significant mechanical obstructions affecting ventricular filling or outflow or both. 6. Treatment limitation decision in place (e.g. DNAR or not for ventilation/ dialysis). 7. Known or estimated weight >135kg. 8. Known to be pregnant. 9. Previous treatment with levosimendan within 30 days. 10. Known hypersensitivity to levosimendan or any of the excipients 111.Known to have received another investigational medicinal product within 30 days or currently in another interventional trial that might interact with the study drug.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome will compare mean Sequential Organ Failure Assessment (SOFA) score after randomisation between treatment groups. This is a well validated scoring system assessing the severity of organ failures. The mean SOFA is predictive of mortality regardless of ICU length of stay and therefore no imputation for death is required. All SOFA scores while alive in ICU (excluding neurological component) will be used for all patients to calculate the mean SOFA score for each patient. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
CARDIOVASCULAR - Central venous oxygen saturations and cardiac output
RENAL - Stage of Acute Kidney Injury
RESPIRATORY - Time to extubation
OTHER CLINICAL OUTCOMES 28-day, hospital and three & six-month survival ICU and hospital length of stay, and ICU-free days Duration of renal replacement therapy Days free from catecholamine therapy
Blood and urinary biomarkers
PHARMACOKINETICS |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
CARDIOVASCULAR - Over the first 96 hours
RENAL - at Day 14 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 26 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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This study will end when the specified number of patients have been recruited and all patients have completed 6 month follow-up and the database is locked.. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 29 |